OUTCOME OF PATIENTS WITH NEWLY DIAGNOSED PRIMARY CNS LYMPHOMA AFTER HIGH‐DOSE METHOTREXATE FOLLOWED BY CONSOLIDATION WHOLE‐BRAIN RADIOTHERAPY AND CYTARABINE

AbstractWith the exception of high-dose methotrexate (HD-MTX), there is currently no defined standard treatment for newly diagnosed primary central nervous system lymphoma (PCNSL). This review focused on first-line induction and consolidation treatment of PCNSL and aimed to determine the optimal combination of HD-MTX and the long-term beneficial consolidation methods. A comprehensive literature search of MEDLINE identified 1407 studies, among which 31 studies met the inclusion criteria. The meta-analysis was performed by using Stata SE version 15. Forest plots were generated to report combined outcomes like the complete response rate (CRR), overall survival, and progression-free survival. We also conducted univariate regression analyses of the baseline characteristics to identify the source of heterogeneity. Pooled analysis showed a CRR of 41% across all HD-MTX-based regimens, and three- and four-drug regimens had better CRRs than HD-MTX monotherapy. In all combinations based on HD-MTX, the HD-MTX + procarbazine + vincristine (MPV) regimen showed pooled CRRs of 63% and 58% with and without rituximab, respectively, followed by the rituximab + HD-MTX + temozolomide regimen, which showed a pooled CRR of 60%. Pooled PFS and OS showed that post-remission consolidation with autologous stem cell transplantation (ASCT) was associated with the best survival outcome, with a pooled 2-year OS of 80%, a 2-year PFS of 74%, a 5-year OS of 77%, and a 5-year PFS of 63%. Next, whole-brain radiation therapy (WBRT) + chemotherapy showed a pooled 2-year OS of 72%, 2-year PFS of 56%, 5-year OS of 55%, and 5-year PFS of 41%, with no detectable CR heterogeneity throughout the entire treatment process. In HD-MTX-based therapy of newly diagnosed PCNSL, MPV with or without rituximab can be chosen as the inductive regimen, and the rituximab + HD-MTX + temozolomide regimen is also a practical choice. Based on our study, high-dose chemotherapy supported by ASCT is an efficacious approach for consolidation. Consolidation with WBRT + chemotherapy can be another feasible approach.

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A prospective phase II trial of response adapted whole brain radiotherapy after high dose methotrexate based chemotherapy in patients with newly diagnosed primary central nervous system lymphoma-analysis of acute toxicity profile and early clinical outcome

Journal of Neuro-Oncology ◽

10.1007/s11060-018-2856-y ◽

2018 ◽

Vol 139 (1) ◽

pp. 153-166 ◽

Cited By ~ 6

Author(s):

Narayan Adhikari ◽

Ahitagni Biswas ◽

Ajay Gogia ◽

Ranjit Kumar Sahoo ◽

Ajay Garg ◽

...

Keyword(s):

Phase Ii Trial ◽

Central Nervous System Lymphoma ◽

Whole Brain Radiotherapy ◽

High Dose ◽

High Dose Methotrexate ◽

Toxicity Profile ◽

Newly Diagnosed ◽

Brain Radiotherapy ◽

Dose Methotrexate ◽

Prospective Phase

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Combined immunochemotherapy with reduced dose whole brain radiotherapy (WBRT) for newly diagnosed patients with primary CNS lymphoma (PCNSL)

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.14_suppl.1518 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 1518-1518

Author(s):

F. G. El Kamar ◽

L. M. Deangelis ◽

J. Yahalom ◽

D. D. Correa ◽

B. W. Grant ◽

...

Keyword(s):

Primary Cns Lymphoma ◽

Whole Brain Radiotherapy ◽

Cns Lymphoma ◽

Newly Diagnosed ◽

Whole Brain ◽

Reduced Dose ◽

Brain Radiotherapy

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Combined immunochemotherapy with reduced dose whole brain radiotherapy (WBRT) for newly diagnosed patients with primary CNS lymphoma (PCNSL)

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.90140.1518 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 1518-1518

Author(s):

F. G. El Kamar ◽

L. M. Deangelis ◽

J. Yahalom ◽

D. D. Correa ◽

B. W. Grant ◽

...

Keyword(s):

Primary Cns Lymphoma ◽

Whole Brain Radiotherapy ◽

Cns Lymphoma ◽

Newly Diagnosed ◽

Whole Brain ◽

Reduced Dose ◽

Brain Radiotherapy

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Treatment of primary CNS lymphoma with induction high-dose methotrexate, temozolomide, rituximab followed by consolidation cytarabine/etoposide: A pilot study with biomarker analysis

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7595 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7595-7595 ◽

Cited By ~ 1

Author(s):

S. Issa ◽

J. Hwang ◽

J. Karch ◽

J. Fridlyand ◽

M. Prados ◽

...

Keyword(s):

Induction Therapy ◽

Primary Cns Lymphoma ◽

Cns Lymphoma ◽

High Dose ◽

High Dose Methotrexate ◽

Whole Brain Irradiation ◽

Whole Brain ◽

Brain Irradiation ◽

Dose Methotrexate ◽

Biomarker Analysis

7595 Background: There is currently no consensus on the optimal treatment for patients diagnosed with primary CNS lymphoma (PCNSL). Between 2001–2004, UCSF PCNSL patients were treated with combination high-dose methotrexate, temozolomide, rituximab (MTR) as induction therapy. Patients in CR with this regimen were treated with high-dose cytarabine plus etoposide as consolidation. The purposes of this study were: (1) Pilot analysis to determine the safety and efficacy of intensive methotrexate-based induction therapy followed by high-dose consolidation with elimination of whole brain irradiation; (2) Analysis of molecular markers in PCNSL which predict sensitivity to chemotherapy and outcome. Methods: 21 untreated, CD20 +, immunocompetent PCNSL patients were treated with combination methotrexate (8 gm/m²), temozolomide (150 mg/m²/day)and rituximab (375 mg/m²). Patients in CR received consolidation cytarabine (2 g/ m² x 8 doses) plus etoposide (40 mg/kg over 96 hours). IHC analysis of potential biomarkers predictive of outcome was performed on paraffin sections from these patients. Candidate markers for validation were selected by gene expression analysis of an independent, multicenter dataset of 20 cases. Results: Mean age was 58.6 y (range 40–81). Median KPS was 60. MTR and cytarabine/etoposide consolidation was well-tolerated with no treatment-related mortality or evidence for neurotoxicity. One case of post-remission cytopenia occurred after consolidation and resolved spontaneously. Eleven patients (52.4%) attained CR with induction; eight received consolidation; three patients in CR deferred consolidation. Median PFS was 11.5 months. Median OS for all 21 patients has not yet been reached with median follow-up of 27.5 months. Expression of the apoptotic regulator DAP-1 by lymphoma cells as determined by IHC was associated with improved PFS (p<0.028) and OS (p<0.021). Conclusions: Combination MTR followed by intensive consolidation appears to be well tolerated in PCNSL. PFS appears at least similar to regimens that contain whole brain irradiation. A larger phase II study has been initiated to evaluate this regimen in a multicenter setting. [Table: see text]

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Randomized phase III study of high-dose methotrexate and whole brain radiotherapy with or without concomitant and adjuvant temozolomide in patients with newly diagnosed primary central nervous system lymphoma: JCOG1114C.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.2500 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 2500-2500

Author(s):

Kazuhiko Mishima ◽

Ryo Nishikawa ◽

Yoshitaka Narita ◽

Junki Mizusawa ◽

Minako Sumi ◽

...

Keyword(s):

Central Nervous System ◽

Central Nervous System Lymphoma ◽

Whole Brain Radiotherapy ◽

Hazard Ratio ◽

Phase Iii ◽

High Dose ◽

High Dose Methotrexate ◽

Newly Diagnosed ◽

Brain Radiotherapy ◽

Dose Methotrexate

2500 Background: Temozolomide (TMZ) is an oral alkylating agent that penetrates the blood-brain barrier with moderate toxicity, and has shown anti-tumor activity in primary central nervous system lymphoma (PCNSL) in single arm studies. Our goal was to determine whether the addition of concomitant and adjuvant TMZ chemotherapy to standard treatment of high-dose methotrexate (HD-MTX) and whole brain radiotherapy (WBRT) for PCNSL improves survival in a randomized controlled trial. Methods: We did an open-label, randomized phase III trial at 30 hospitals in Japan enrolling immunocompetent patients (pts) aged 20-70 years with histologically confirmed newly diagnosed PCNSL. Pts enrolled at step 1 registration received HD-MTX (MTX; 3.5 g/m2 at day 1, 15, 29). Pts who received at least 1 cycle of HD-MTX were randomly assigned (1:1) at step 2 registration to receive WBRT (30 Gy) ± 10 Gy boost (control arm: A) or WBRT ± boost with concomitant TMZ (75 mg/m2 daily) and adjuvant TMZ (150-200 mg/m2 daily for 5 days every 28 days) for two years after initiation of HD-MTX or until tumor progression (experimental arm: B). Randomization was adjusted by institution, PS (0-1 / 2-3), age (≤60/≥61 years), presence or absence of intraparenchymal tumor after HD-MTX. The primary endpoint was overall survival (OS). The planned sample size was 130 pts in total, to provide an 80% power to detect a 0.52 hazard ratio (65% vs 80% in 2y-OS) for arm B to A and a one-sided alpha of 5%. Results: Between September 29, 2014 and October 15, 2018, 134 pts were enrolled, of whom 122 were randomly assigned and analyzed; 62 to arm A and 60 to arm B. At the planned interim analysis, the 2-y OS was 86.8% (95% CI: 72.5-94.0) in arm A and 71.4% (56.0-82.2) in arm B. The hazard ratio was 2.18 (95% CI: 0.95 to 4.98) with predictive probability for showing the superiority of arm B at the final analysis was calculated to be 1.3%. The study was terminated due to futility. The 2-y progression-free survival was 60.6% (43.6-73.8) in arm A and 49.9% (34.4-63.5) in arm B with a hazard ratio of 1.54 (0.88 to 2.70). The most common grade 3 and 4 toxicities were lymphopenia, observed in 7 (11.5%) pts during WBRT in arm A, 18 (30%) pts during WBRT + concomitant TMZ and 18 (37.5%) pts during adjuvant TMZ in arm B. Conclusions: This study failed to demonstrate the benefit of the addition of TMZ to WBRT and adjuvant TMZ in newly diagnosed PCNSL. Possible biomarkers including methylation status of the MGMT promoter in the tumors will be analyzed. Clinical trial information: jRCTs031180207 .

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